Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by a loss of substantia nigra pars compacta neurons, which currently affects 1.5 million people in the United States. Although rare mutations associated with familial forms of PD have been identified most cases occur sporadically. While the causes of PD are unknown, a critical role of environmental factors either alone, or in combination with genetic susceptibilities is implicated in disease pathogenesis. Major pathologic mechanisms that lead to neurodegenerative phenotype of nigrostriatal dopaminergic neurons include mitochondrial dysfunction, oxidative damage, impairments of key cell survival signaling, and activation of inherent cell death pathways. Epidemiological studies have identified pesticides as potential environmental exposures that influence the risk of PD. Our preliminary data suggest that oral administration of pesticides in mice cause degeneration of nigrostriatal dopaminergic neurons, striatal loss of dopamine and its metabolites, pathologic accumulation of 1-synuclein and oxidative damage. We hypothesize that administration of these pesticides cause neurodegeneration due to mitochondrial dysfunction, and by activation or impairment of signal transduction pathways that are detrimental for normal functioning of dopaminergic neurons. Additionally, these pathologic mechanisms may lead to exacerbation of neurodegeneration in transgenic mouse models of familial PD. Three specific aims are proposed to test the hypothesis. Aim 1 will study the identification and validation of key cell signaling pathways that lead to nigrostriatal dopaminergic neurodegeneration due to pesticide exposure in mice. Aim 2 will study the role of transcriptional regulation of key cell signaling pathways such as Nrf2/ARE, PGC-1 alpha and SIRT1 in addition to specific signal transduction pathways identified and validated in Aim 1 on mitochondrial function and neuropathological features involved in disease development due to pesticide exposure in mice. Aim 3 will examine the role of pesticide exposures in transgenic mouse models of familial PD to assess mitochondrial function, cell signaling pathways leading to exacerbation of nigrostriatal dopaminergic neurons and behavioral abnormalities. These studies will provide us with novel mechanistic insights to events leading to disease development in both sporadic and familial forms of PD due to pesticide exposure and will enable us identify potential links between gene environment interactions in PD. PUBLIC HEALTH RELEVANCE: This study proposes to identify novel signal transduction pathways in wild type and transgenic mice harboring familial PD mutations for onset and development of Parkinson's disease (PD) due to exposure of mitochondria targeted pesticide. The study will enrich and refine our understanding of pesticide-induced cell damage pathways observed in sporadic and familial PD and identify new target(s) for intervention in PD pathogenesis.